Parkinson's disease (PD), a late-life movement disorder affecting >500,000 individuals, it is associated with abnormalities of dopaminergic neurons in the substantia nigra, pars compacta (SNpc) and loss of dopaminergic terminals in striatum. Although the causes of the majority of cases of PD are not known, genetic studies of familial PD (<10% of total cases of PD) have recently identified a missense mutation (A53T) in alpha-Synuclein (alpha-Syn). Moreover, alpha-Syn accumulates in Lewy bodies (LB), cytoplasmic inclusions characteristic of familial and sporadic PD. These findings indicate that alpha-Syn is an important component in the pathogenesis of disease. Although the functions of alpha-Syn are not known, it is abundant in neurons and is particularly enriched in the presynaptic terminals. In humans and rodents, beta Syn and gamma-Syn, members of the Syn family, are also expressed in nervous tissues. To gain a better understanding of the roles of different Syn isotypes in normal neuronal functions and the pathogenesis of PD, we will examine the expression patterns and cell biology of different Syn in human and rodent tissues, and in transgenic (Tg) mice expressing wild-type or A53T alpha- Syn, and in transfected cells in vitro. Specifically, we propose: to determine the levels of expression and localization of Syn isotypes in specific brain regions and neural systems in rodents and humans during development and aging; to generate Tg mice expressing high levels of wild- type or A53T human alpha-Syn and to analyze the character/evolution of abnormalities in mice that over-express the mutant; to study the expression, metabolism, and subcellular localization of Syn isotype in lines of cultured cells and in primary neuronal cultures from Tg mice; and to define the axonal transport and metabolism of endogenous and transgene- encoded Syn in vivo. The results of these studies will provide information critical to understanding the roles of Syn in normal brain and the behavior of A53T alpha-Syn in vitro and in vivo model systems, particularly in Tg mice. Information about the mechanisms of disease will then be translated into the design of new therapies that can be tested in model systems.